Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs

Mol Brain. 2020 Feb 19;13(1):18. doi: 10.1186/s13041-020-0561-1.


Spinal bulbar muscular atrophy (SBMA) is an adult-onset, slowly progressive motor neuron disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. Thus, novel human disease models that recapitulate SBMA patients' pathology more accurately are required for more precise pathophysiological analysis and the development of novel therapeutics. Here, we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. To investigate motor neuron specific pathology, we purified iPSC-derived motor neurons using flow cytometry and cell sorting based on the motor neuron specific reporter, HB9e438::Venus, and proceeded to the genome-wide transcriptome analysis by RNA sequences. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. Notably, we demonstrated the involvement of the neuromuscular synapse via significant upregulation of Synaptotagmin, R-Spondin2 (RSPO2), and WNT ligands in motor neurons derived from SBMA patients, which are known to be associated with neuromuscular junction (NMJ) formation and acetylcholine receptor (AChR) clustering. These aberrant gene expression in neuromuscular synapses might represent a novel therapeutic target for SBMA.

Keywords: Endoplasmic reticulum; Epigenetics; Gene set enrichment analysis; Induced pluripotent stem cells; Neuromuscular junctions; Neurotransmitter; RNA sequencing; Spinal bulbar muscular atrophy; Synapse; iPSC-derived motor neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cells, Cultured
  • Cellular Reprogramming Techniques
  • Fibroblasts
  • Gene Expression Profiling*
  • Gene Ontology
  • Genome-Wide Association Study
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Motor Neurons
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / pathology*
  • Neurogenesis
  • Synapses / pathology*
  • Transcription Factors / physiology
  • Trinucleotide Repeat Expansion
  • Young Adult


  • Transcription Factors